Human Molecular Genetics Advance Access published online on September 7, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl242
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1 Department of Laboratory Medicine, University of Washington Medical Center, Seattle, WA, USA
* To whom correspondence should be addressed. Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar aggregates of
Received August 7, 2006
Revised August 25, 2006
Accepted September 4, 2006
Article
Yuxin Fan 1, Pornprot Limprasert 1, Ian V.J. Murray 2, Annette C. Smith 1, Virginia M.-Y. Lee 2, John Q. Trojanowski 3, Bryce L. Sopher 1, and Albert R. La Spada 4 *
-synuclein modulates 
-synuclein neurotoxicity by reducing -synuclein protein expression
2 Center for Neurodegenerative Disease Research in the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
3 Center for Neurodegenerative Disease Research in the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute on Aging, University of Pennsylvania, Philadelphia, PA, USA
4 Department of Laboratory Medicine, University of Washington Medical Center, Box 357110, Room NW 120, Seattle, WA 98195-7110; Department of Medicine, University of Washington Medical Center, Seattle, WA, USA; Department of Neurology, University of Washington Medical Center, Seattle, WA, USA; Center for Neurogenetics & Neurotherapeutics, University of Washington Medical Center, Seattle, WA, USA
Albert R. La Spada, E-mail: laspada{at}u.washington.edu
Abstract 
-synuclein in characteristic inclusions known as 'Lewy bodies'. As mutations altering -synuclein structure or increasing -synuclein expression level can cause familial forms of PD or related Lewy body disorders, -synuclein is believed to play a central role in the process of neuron toxicity, degeneration, and death in "synucleinopathies". ?
-synuclein is closely related to -synuclein, and has been shown to inhibit -synuclein aggregation and ameliorate -synuclein neurotoxicity. We generated -synuclein transgenic mice, and observed a marked reduction in -synuclein protein expression in the cortex of mice over-expressing -synuclein. This reduction in -synuclein protein expression was not accompanied by decreases in -synuclein mRNA expression. Using the prion protein promoter -synuclein A53T mouse model of PD, we demonstrated that over-expression of -synuclein could retard the progression of impaired motor performance, reduce -synuclein aggregation, and extend survival in doubly transgenic mice. We attributed the amelioration of -synuclein neurotoxicity in such bigenic mice to the ability of -synuclein to reduce -synuclein protein expression based upon I125 autoradiography quantification. Our findings indicate that increased expression of -synuclein protein results in a reduction of -synuclein protein expression. As increased expression of -synuclein may cause or contribute to PD pathogenesis in sporadic and familial forms of disease, this observation has important implications for the development of therapies for PD.
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